Posted on Saturday 24 October 2015

Early in October, I had a a touch of paralysis… I had read an article in the American Journal of Psychiatry
by D. Jeffrey Newport, Linda L. Carpenter, William M. McDonald, James B. Potash, Mauricio Tohen, and Charles B. Nemeroff, The APA Council of Research Task Force on Novel Biomarkers and Treatments
American Journal of Psychiatry. 2015 172:950–966.

… Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, D-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects.
Conclusions: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.
… and had a reaction. It felt like I was reading the script for a television infomercial rather than a scientific article. On the surface, it was a meta-analysis of the studies about Ketamine and related drugs, but there was one in particular that I thought was being inappropriately hyped – rapastinel [GLYX-13]. I couldn’t prove it, but my index of suspicion was as high as it gets [particularly a Nemeroff with a big COI section]. Here’s an article I ran across last night that documents how rampant these subtle infomercial meta-analyses have become – specifically in the antidepressant drug literature:
by Shanil Ebrahim, Sheena Bance, Abha Athale, Cindy Malachowski, and, John P.A. Ioannidis
Journal of Clinical Epidemiology. Published on-line September 21, 2015.

Objectives: To identify the impact of industry involvement in the publication and interpretation of meta-analyses of antidepressant tri- als in depression.
Study Design and Setting: Using MEDLINE, we identified all meta-analyses evaluating antidepressants for depression published in January 2007 – March 2014. We extracted data pertaining to author affiliations, conflicts of interest, and whether the conclusion of the ab- stract included negative statements on whether the antidepressant[s] were effective or safe.
Results: We identified 185 eligible meta-analyses. Fifty-four meta-analyses [29%] had authors who were employees of the assessed drug manufacturer, and 147 [79%] had some industry link [sponsorship or authors who were industry employees and/or had conflicts of interest]. Only 58 meta-analyses [31%] had negative statements in the concluding statement of the abstract. Meta-analyses including an author who were employees of the manufacturer of the assessed drug were 22-fold less likely to have negative statements about the drug than other meta-analyses [1/54 [2%] vs. 57/131 [44%]; P < 0.001].
Conclusion: There is a massive production of meta-analyses of antidepressants for depression authored by or linked to the industry, and they almost never report any caveats about antidepressants in their abstracts. Our findings add a note of caution for meta-analyses with ties to the manufacturers of the assessed products.
I hope people haven’t forgotten the bruhaha around this same issue in the New England Journal earlier this year. The New England Journal of Medicine had a strict policy against authors with COI writing review [or meta-analysis] articles:
"In 1984, the late Arnold S. Relman, then the NEJM’s editor in chief, instituted the first conflict of interest policy at any major medical journal. The policy required authors of research papers to disclose all financial ties they had to health industries, and if the ties were deemed significant they were published. In 1990, Relman extended the policy to prohibit authors of editorials and review articles from having any financial interest in a company [or its competitor] that was discussed in the article, since these types of manuscripts do not contain primary data but rely exclusively on the authors’ judgment in citing and interpreting the literature…" [reference]
In May of this year, the current NEJM Editor, Jeffrey Drazen, wrote an editorial suggesting that they change this policy, and it was supported in a three part series by NEJM reporter, Lisa Rosenbaum:
This was one of those issues I couldn’t seem to stop protesting:
And I certainly wasn’t alone. Here are some of the responses – one by Roy Poses of Healthcare Renewal, and two others from the former editors of the New England Journal of Medicine and the current editors of the British Medical Journal:
But the best argument against Dr. Drazen’s suggestion is this current article by John Ioannidis and his colleagues. They end with "a note of caution for meta-analyses with ties to the manufacturers of the assessed products." I would perhaps use stronger language. This kind of KOL authored review/meta-analysis article that has a commercial thrust cloaked in science has become a racket, that offers a big payoff for the industry sponsors. It’s subliminal advertising at its best because we read review articles. It’s hard for busy practitioners to keep current, and review articles are "just what the doctor ordered" – an overview by "experts." So I hope this article in the Journal of Clinical Epidemiology is widely read. It documents the broad extent of the problem [I got the link from James Coyne’s Twitter feed]. And by the way, in case I didn’t say it directly, the New England Journal of Medicine’s policy should be an  example for the rest of the peer-reviewed academic journals rather that something to be considering changing…
    Bernard Carroll
    October 24, 2015 | 11:22 AM

    Two aphorisms come to mind: Nihil sub sole novum, and Human nature doesn’t change. These are precisely the issues raised about COI in review articles by Robert Rubin and myself over a decade ago. That became a cause celèbre, exposed in The New York Times, and it forced Nature Publishing Group (after much stonewalling) to change its policy on declaring COI for review articles – despite Charles Nemeroff kicking and screaming and pointing the finger back at NPG. Meanwhile, American Journal of Psychiatry doesn’t seem to have got the message that simply declaring COI is not the solution – it allows the bias and spin to continue in plain sight.

    October 24, 2015 | 1:52 PM

    Geez, didn’t LSD at one point have some questionable therapeutic efficacy?

    And, dentist still use cocaine for their practices, true?

    The more things change the more they seem to stay the same….

    Better living thru chemistry, eh?

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